CCRC AcuteCoron Slides T199174 Final-1up

Complex Case:
Acute Coronary Syndrome
Jill H. Starykowicz, Pharm.D., BCCCP
Clinical Pharmacy Specialist, Cardiology/Critical Care
Advocate Lutheran General Hospital
Park Ridge, Illinois
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©2019 American Society of Health-System Pharmacists, Inc. All rights reserved. 1
Disclosure
• All planners, presenters, and reviewers of this
session report no financial relationships
relevant to this activity.
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Learning Objectives
• Develop appropriate treatment and monitoring
plans for a complex critical care patient with
acute coronary syndrome (ACS).
• Modify treatment and monitoring plans related
to alterations of pharmacodynamics and
pharmacokinetics in the critically ill.
• Select appropriate devices required for treatment
and monitoring of a critical care patient
• Identify appropriate fluid and electrolyte
management and monitoring based on patient
specific factors.
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Case
• 58‐year‐old African‐American male
– Found unconscious with no pulse
– Bystander CPR initiated, EMS arrives and found to
have ventricular fibrillation (VF)* on ECG
• Treatments given while in ambulance:
– 3 cycles of CPR including defibrillation x 3,
epinephrine 1 mg IV push x 3
– ROSC achieved after approximately 15 minutes
*Refer to ASHP Core Therapeutic Module:
Cardiac Arrhythmias and Advanced Cardiac Life Support
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Case
• Past Medical History:
– Hypertension
– Dyslipidemia
– TIA—2 years ago
• Current Medications:
– Aspirin 81 mg orally once daily
– Lisinopril 20 mg orally once daily
– Atorvastatin 40 mg orally once daily
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Case: STEMI
• ECG: ST‐elevations from V1‐V4 with reciprocal
changes in the inferior leads
• Laboratory Data:
– Troponin T: 95.43 ng/mL
– CK‐MB: 245 ng/mL
– CK: 1475 ng/mL
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Case: STEMI
• Laboratory Data
– ABG: 7.19/36/90/14 with a lactate of 9.2 mmol/L
13.8
Calcium: 7 mg/dL
144 107 27
145 Magnesium: 2.1 mg/dL 7.5 251
3.4 24 1.99 Phosphorus: 4 mg/dL
43.2
– AST 550 unit/L, ALT 120 unit/L
• Vital signs immediately post intubation
– RR 20, Pulse 88 bpm, regular, BP 125/59 mm Hg,
Temperature 37.2⁰C, O2 Sat 95%
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Case: ST‐Elevation Myocardial
Infarction (STEMI)
• Physical Exam:
– General: Intubated and sedated
– HEENT: pupils are equal, round, and reactive to light
– Pulmonary: Mild inspiratory and expiratory crackles ¼ of the
way up both lung fields bilaterally
– Cardiovascular: RRR, no murmur, normal peripheral perfusion
– GI: soft, tender, nondistended, normal bowel sounds
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Acute Coronary Syndromes
Clinical suspicion of ACS (based on signs/symptoms)
• Chest pain/discomfort radiating to neck, jaw, or shoulders that is non‐traumatic in
origin or anginal equivalents which include persistent shortness of breath,
nausea/vomiting, indigestion, or new onset weakness
• Keep in mind women, elderly or those patients with diabetes may present with
atypical symptoms
• High suspicion for ACS should be given to those with a history of CAD with or without
prior ACS or CABG
Positive 12‐Lead ECG
Negative 12‐Lead ECG
• ST‐segment elevation in two or more
• Minimal or ischemic changes that may
contiguous leads
include T‐wave inversion or ST‐segment
• New Left Bundle Branch Block
depression (other than in leads V2 or V3
• ST‐depression in leads V2 and V3 (posterior MI)
Cardiac Enzymes Positive Cardiac Enzymes Positive Cardiac Enzymes Negative
Unstable Angina
STEMI NSTEMI
Circulation 2013;127:e362‐425.
Acute Myocardial Infarctions Circulation 2014;130:e344‐426.
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Causes of Elevated Troponin
• Acute MI • Chronic heart failure
• Post‐PCI • ADHF
• Early post‐cardiac surgery • Chest wall syndrome
• Acute PE • Strenuous exercise
• Rhabdomyolysis • Cardiotoxic
• Tachyarrhythmia chemotherapy
• Aortic stenosis • Defibrillation/ direct
current cardioversion
• Pericarditis
• Cardiac amyloidosis
• Myocarditis
• Heart transplantation
• Type A dissection
• Sepsis
Heart 2006;92:987‐93.
Crit Care Med 2007;35:584‐88.
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ACS Management
Type of MI STEMI NSTEMI
Goals of Early reperfusion as soon as possible Prevent total occlusion of
care coronary vessel
• Primary PCI preferred if performed
within 90 minutes • Decision and need for
revascularization (PCI vs.
• If primary PCI is unavailable within 90
surgery) vs. medical
minutes thrombolytics should be
management should be
administered within 30 minutes of
made on the basis of risk
presentation unless contraindications
stratification, symptom
exist
resolution, and indicators of
• Surgical revascularization may be ongoing myocardial
indicated, depending on severity of ischemia
CAD, complexity of anatomy or
development of complications
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ACS Interventions
Intervention Clinical pearl
• Provides anginal pain relief due to tissue hypoxia
Oxygen • Consider administration is SaO2 is less than 90%, respiratory distress or
other high‐risk features of hypoxemia
• Inhibits platelet activation
Aspirin • Administer 81 mg x 4 chew tabs (324 mg) orally or 300 mg rectally if unable
to take oral
• Coronary vasodilator, can also be used with severe cardiogenic pulmonary
edema
• Nitroglycerin 0.4 mg sublingually every minute for a total of 3 doses; assess
Nitrates need for intravenous nitroglycerin
• IV nitroglycerin is indicated for first 48 hours after treatment of persistent
ischemia, HF, or hypotension but should not preclude administration with a
β‐blocker or ACE inhibitor when appropriate
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ACS Interventions
Intervention Clinical Pearl
Morphine/ • Provides analgesia and decreases pain‐induced sympathetic tone
Narcotic • Morphine commonly used because it causes vasodilation and some degree
analgesic of afterload reduction
β‐blockade • Decreases heart rate and myocardial oxygen demand and increases diastolic
filling time of ventricles and coronary arteries
• Should be initiated within the first 24 hours of an ACS unless:
1. Signs of HF
2. Active evidence of hemodynamic instability/ shock
3. Increased risk of cardiogenic shock (SBP < 120 mm Hg, heart rate
>110 bpm, or <60 bpm)
• Relative contraindications
1. PR interval greater than 0.24 sec, 2nd or 3rd degree heart block, active
asthma or reactive airway disease
Loop diuretics May be used in cases of sever cardiopulmonary edema or other symptoms of
HF with volume overload
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Non‐Surgical Revascularization
Intervention Clinical pearl
Thrombectomy • Tissue aspiration followed by placement of a stent at the site of the
coronary lesion
Balloon angioplasty • Balloon expansion to displace an occlusion at the site of the lesion
Stent Placement • Bare metal stent
• Requires aspirin indefinitely and a P2Y12 antagonist for at least
Number, placement 12 months (in certain situations may be a shorter duration or
or location? longer duration depending on the number or type of stent(s)
placed)
• Higher risk of in‐stent stenosis as re‐endothelialization occurs
• Drug‐eluting stent
• Requires aspirin indefinitely and a P2Y12 antagonist for at least
12 months (in certain situations may be longer duration
depending on the number or type of stent(s) placed)
• Ongoing investigation regarding optimal duration of dual
antiplatelet therapy
• Higher risk of stent thrombosis; endothelialization is slowed due
to drug coating over stent
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Antiplatelet and Antithrombotic Administration
Coagulation Cascade Platelet
Leukocytes
Collagen
Tissue Factor LMWH
Platelets
LMWH TFPI
UFH Thromboxane A2 ADP
Factor Xa vWF
Aspirin
Activated platelet P2Y12
LMWH Prothrombin
Inhibitors
UFH GPIIb/IIIa
Inhibitors Fibrinogen cross‐linking
Thrombin
Direct Platelet aggregation
Thrombin
Inhibitors Plasmin Fibrin
Fibrin Thrombus Degradation
Fibrinogen
Fibrinolytics
Selwyn AP. Am J Cardiol 2003:91(suppl):3H‐11H
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Question 1: Which of the following is the
preferred initial oral antiplatelet treatment for
this patient?
A. Aspirin 325 mg and clopidogrel 600 mg x 1
B. Aspirin 325 mg and prasugrel 60 mg x 1
C. Aspirin 325 mg and ticagrelor 180 mg x 1
D. Aspirin 81 mg and ticagrelor 180 mg x 1
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Duration of DAPT in ACS Treated with PCI
• In patients with ACS (NSTE‐ACS or STEMI) treated with DAPT
I B‐R after BMS or DES implantation, P2Y12 inhibitor therapy
(clopidogrel, prasugrel or ticagrelor should be given for at least
12 months.
• In patients treated with DAPT, a daily aspirin dose of 81 mg is
I B‐R recommended.
• In patients with ACS (NSTE‐ACS or STEMI) treated with coronary
stent implantation who have tolerated DAPT without a bleeding
IIb A SR
complication and who are not at high risk of bleeding,
continuation of DAPT for longer than 12 months may be
reasonable.
• In patients with ACS (NSTE‐ACS or STEMI) after DES who
develop a high risk of bleeding (e.g., treatment with oral
IIb C‐LD anticoagulant therapy), are at high risk of severe bleeding
complication (e.g., major intracranial surgery), or develop
significant overt bleeding, discontinuation of P2Y12 inhibitor
therapy after 6 months may be reasonable.
Levine GN, et al. JACC. 2016;68:1082‐115.
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Recommendations for P2Y12 Inhibitors
• In patients with ACS treated with DAPT after coronary stent
IIa B‐R
implantation it is reasonable to use ticagrelor in preference
to clopidogrel for maintenance P2Y12 inhibitor therapy.
• In patients with ACS (NSTE‐ACS or STEMI) treated with
IIa B‐R DAPT after coronary stent implantation who are not at high
risk for bleeding complications and who do not have a
history of stroke or TIA, it is reasonable to choose prasugrel
over clopidogrel for maintenance P2Y12 inhibitor therapy.
III: Harm B‐R
• Prasugrel should not be administered to patients with a
prior history of stroke or TIA.
Levine GN, et al. JACC. 2016;68:1082‐115.
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Clopidogrel in ACS
• Benefits seen with non‐ST elevation ACS
– CURE, PCI‐CURE, CREDO studies
– Reduction in death, myocardial infarction (MI), and stroke
• Benefits seen with STEMI ACS
– CLARITY, COMMIT studies
– Reduction in death, MI, stroke
• Clinical controversy—variability of platelet inhibition,
genetic polymorphisms
Yusuf S et al. Circulation. 2003; 107:966‐72.
Mehta S et al. Lancet 2001; 358;527‐33.
Steinhubl SR et al. JAMA. 2002; 288:2411‐20.
Sabatine MS et al. N Engl J Med. 2005; 352:1179‐89.
Chen Z et al. Lancet. 2005; 366:1607‐21.
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Prasugrel in ACS
• Rapid and extensive platelet inhibition
• Lack of drug interactions
• Lack of genetic determinants
• Improvements in clinical outcomes over clopidogrel
– Demonstrated in diabetic population
• Clinical concerns/ controversy
– Higher bleeding rates than clopidogrel
– Contraindicated with history of TIA or stroke
– No net clinical benefit seen with age >75 years or weight
<60 kg
Wiviott SD et al. N Engl J Med 2007; 357:2001‐15.
Wiviott SD et al. Circulation. 2008; 118:1626‐36.
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Ticagrelor in ACS
• Superiority over clopidogrel in medical and invasive
management
– Significant reduction in cardiovascular death and MI
• Minimal increase in bleeding compared with
clopidogrel
– Seen with TIMI non‐CABG major bleeding
• Clinical considerations/controversy
– Significant drug‐drug interactions with CYP3A4 inhibitors
and P‐glycoprotein
– ADE—dyspnea and ventricular pauses
– Cannot exceed aspirin maintenance doses of 100 mg
– Twice daily dosing
Wallentin L et al. N Engl J Med. 2009; 361:1045-57.

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Cangrelor
• First intravenous P2Y12 inhibitor approved for use for PCI
– Bolus prior to PCI: 30 mcg/kg IV push followed by a continuous infusion
starting at 4 mcg/kg/min
– Maintenance infusion should be continued for at least 2 hours or for
the duration of the PCI (whichever is longer)
• Two clinical reviews published in response to NDA stating there is no
superiority or inferiority of cangrelor vs clopidogrel
– Delays in clopidogrel administration in CHAMPION
PCI/PLATFORM/PHOENIX
– Dose of clopidogrel used is less than the recommended dosing
– PHOENIX prohibited prasugrel, ticagrelor or GPI (glycoprotein inhibitor)
• Overall negative results in CHAMION PCI and PLATFORM
– 2014: FDA rejected initial approval for PCI and bridging indications due
to lack of benefit and evidence Bhatt DL, et al. N Engl J Med 2009;361:2330‐41.
Bhatt DL, et al. N Engl J Med 2013;368:1303‐13.
Harrington RA, et al. N Engl J Med 2009:361:2318‐29.
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Cangrelor: Place in Therapy
• “Hot” lesions that may not require immediate
intervention and GP IIb/IIIa inhibitor is contraindicated
• Patient cannot tolerate oral P2Y12 at time of PCI
and/or for a prolonged duration after intervention
• BRIDGE to CABG: 0.75 mcg/kg/min and discontinued 1
to 6 hours prior to surgery
– Other surgical procedures?
— No published data outside of CABG; limited case reports
— Concern for intraoperative and postoperative bleeding?
– Cost vs. GPI
Angiolillo DJ, et al; JAMA. 2012;307(3):265‐274.
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P2Y12 Inhibitors
Parameter Clopidogrel Prasugrel Ticagrelor Cangrelor
ACS, MI,
FDA‐approved indications ACS ACS ACS
stroke, PAD
Non‐ Non‐
Pharmacologic Class Thienopyridine Thienopyridine
thienopyridine thienopyridine
Route of Administration Oral Oral Oral Intravenous
30 mcg/kg IV
Loading Dose 600 mg 60 mg 180 mg
push
Maintenance Dose 75 mg daily 10 mg daily 90 mg BID NA
Prodrug Yes Yes No No
Onset 2‐8 hours 30‐60 min 30‐60 min 2 min
T ½ 7‐8 hours 7‐8 hours 7‐12 hours 3‐5 min
% Platelet Inhibition 40 70 95 95
Duration to hold prior to
5 days 7 days 3‐5 days 30‐60 min
procedure
Rollini F, et al. Nature Reviews 2016:13;11‐27.
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Question 2: Which of the following anticoagulants
should be initiated in this patient for primary PCI?
A. Enoxaparin IV push x 1
B. Bivalirudin IV push followed by a continuous infusion
C. UFH plus an abciximab bolus and continuous infusion
D. UFH plus an eptifibatide bolus x 2 and continuous
infusion
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Dosing of Anticoagulants: STEMI with Primary PCI
• Anticoagulant Therapy
– UFH
— With GP IIb/IIIa inhibitor: 50‐70 unit/kg IV bolus to achieve
therapeutic activated clotting time (ACT)* (Class I, LOE C)
— With no GP IIb/IIIa inhibitor: 70‐100 unit/kg IV bolus to achieve
therapeutic ACT** (Class I, LOE C)
– Bivalirudin: 0.75 mg/kg IV bolus, then 1.75 mg/kg/hr infusion with or
without prior treatment with UFH. An additional 0.3 mg/kg can be
given if needed (Class I, LOE B)
– Reduce infusion to 1 mg/kg/hr with CrCL < 30 mL/min
– Preferred over UFH with GP IIb/IIIa inhibitor in patients with high bleeding risk
(Class IIa, LOE B)
– Fondaparinux : Not recommended as sole anticoagulant in PCI (Class
III, LOE B)
*The recommended ACT with planned GP IIb/IIIa receptor antagonist treatment is 200 to 250 s.
**The recommended ACT with no planned GP IIb/IIIa receptor antagonist treatment is 250 to 300 s (HemoTec device)
or 300 to 350 s (Hemochron device).
LOE = level of evidence O’Gara PT et al. Circulation. 2013;127:529‐55.
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Bivalirudin vs. UFH
• HORIZONS‐AMI and EUROMAX
– Major bleeding significantly less with bivalirudin use over
UFH for STEMI
– Considerations for approach (femoral vs. radial)
– Clopidogrel only P2Y12 agent administered
– Significant increase in acute in stent thrombosis with those
that received bivalirudin
• All cause mortality reduced in those that received
bivalirudin in HORIZONS‐AMI (p<0.002)
• Composite death or major non‐CABG bleeding
significantly less in those that received bivalirudin in
EUROMAX (p<0.0001)
Stone GW, et al. N Engl J Med 2008;358:2218‐2230.
Steg PG, et al. N Engl J Med 2013;369:2207‐17.
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Bivalirudin vs. UFH
Baseline
Study Intervention Endpoints Outcomes
Characteristics
HEAT‐PPCI Two arms: MACE (death, Clopidogrel 11%, MACE: Bivalirudin 8.7%
1. Bivalirudin w/ CVA, reinfarction, prasugrel 28%, vs. 5.7%, RR 1.54
n= 1812 provisional GPI unplanned ticagrelor 62 % (p=0.01)
2. UFH revascularization) Radial access 80%
STEMI w/provisional GPI: UFH 15% vs Major bleeding: 3.5%
GPI Major bleeding bivalirudin 13% vs. 3.1%
BRAVE‐4 Two arms: Composite death, Trial stopped early Composite: bivalirudin

1. Bivalirudin + MI, unplanned due to low 15.6% vs 14.5%
n= 548 prasugrel w/ revascularization, recruitment (p=0.680)
provisional GPI stent thrombosis,
STEMI 2. UFH + stroke, major Femoral access 99% Major Bleeding 14.1%
clopidogrel bleeding vs. 12% (p=0.543)
w/provisional GPI use: Bivalirudin
GP 3% vs. UFH 6.1%
Shahzad A, et al. Lancet 2014;384:1849‐1858.
Schulz S, et al. Eur Heart J 2014;35:2285‐94.
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Bivalirudin vs. UFH
Baseline
Study Intervention Endpoints Outcomes
Characteristics
MATRIX Two arms: MACE: composite of all‐ Clopidogrel 45%, MACE: bivalirudin 10.3% vs.
1. Bivalirudin + cause death, MI, stroke up Prasugrel 24%, 10.9% (p= 0.44, note: UFH
n= 7213 provisional to 30 days Ticagrelor 13% + planned GPI rate was
GPI (group 8.1%)
STEMI, NSTEMI randomized Net events: major non‐ GPI use: 4.6% vs Net events11.2% vs 12.4%
or PCI to receive CABG bleeding + MACE up 25% (p=0.12)
post PCI to 30 days, Post PCI infusion: 11% vs
bivalirudin x 4 Radial access no infusion 11.9% (p=0.34)
hr vs. placebo Post‐PCI infusion outcome: 50% Major bleeding: 1.4% vs
2. UFH + composite of urgent TVP, 2.5% (p<0.0001)
provisional stent thrombosis or net Death: 1.7% vs 2.3%
GPI adverse clinical events up (p=0.04)
to 30 days
BRIGHT Three arms: Net events: MACE + any STEMI 90% Arm 1 vs. 2: 8.8% vs. 13.2%
1. Bivalirudin + bleeding (p=0.008)
n= 2194
post PCI Clopidogrel 100% Arm 1 vs 3: 8.8% vs 17%
STEMI or NSTEMI infusion MACE (p<0.0001)
and no prior 2. UFH Radial access No difference in MACE
anticoagulation 3. UFH+tirofiban Any bleeding 78.5% Bleeding: 4.1% vs. 7.5% vs.
12.3% (p<0.001)
Valgimigli M, et al. N Engl J Med 2015;373:997‐1009.
Han T, et al. JAMA 2015;313:1336‐1346
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Bivalirudin vs. UFH plus GPI
• Bivalirudin • UFH+ GPI
– Preferred in patients with – Increased risk of bleeding
increased risk of bleeding (radial vs femoral approach)
– Requires renal dosage – Cannot be used with a history
adjustment of/suspicion of HIT
– More data needed with – Frequent monitoring and
newer P2Y12 inhibitors redosing during PCI
– Risk of acute stent – GPI agents may require renal
thrombosis dosage adjustment
• Other considerations with drug selection: type and location of stent,
duration of intervention and cost
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Parenteral Antithrombotic Agents
Medication Heparin Bivalirudin Abciximab Eptifibatide
Loading dose 50 – 100 units/kg 0.75 mg/kg 0.25 mcg/kg 180 mcg/kg
Continuous 0.125 mcg/kg/min 2 mcg/kg/min
Variable 1.75 mg/kg/hr
infusion (max 10 mcg/min) (max 15 mg/hr)
Restoration of
Platelet Irreversible for platelet platelet function 6‐8
NA NA
inhibition lifespan hours once
discontinued
80% plasma proteolysis,
Elimination Hepatic Plasma elimination 70% renal
20% renal
Dialyzable (Y/N) No Yes No Yes
Clinical Pearl • Avoid use in • Requires renal dosage • Murine monoclonal • Requires renal
patients with adjustment for antibody dosage adjustment
history of HIT continuous in • May be used as an • Cannot be used in
• Target ACT • Can be used in patients intracoronary bolus hemodialysis
during with history of HIT patients
procedure 200‐ • May be preferred in • May be used as an
250 sec those with high risk of intracoronary bolus
bleeding
• Target ACT 200‐250 sec
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Tirofiban
• Reversible GPI, approved for use with NSTE‐
ACS
– Dosing: 25 mcg/kg IV bolus within 5 minutes
followed by 0.15 mcg/kg/min for 18 hours
– Requires renal dosage adjustment
– Half life= 2 hours, platelets return to baseline
function 4‐8 hours after discontinuation
• sNDA submitted in 2015 for use with STEMI
based on results from On‐TIME 2
Van’t Hof AW, et al. Lancet 2008;372:537‐46.
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Pharmacogenomic Considerations: ACS
• Genetic risk factors from ACS and drug
therapy
• Variable response to clopidogrel
– Patient phenotype (diabetes mellitus, obesity)
– Enteric ABCB 1 polymorphisms
– CYP 450 enzyme drug interactions and
polymorphisms (CYP 2C19*2)
• Future studies needed to clarify risk
associated with genetic polymorphisms
O’Gara PT et al. Circulation 2013;127:529‐55.
Remmler C and Cascorbi I. Exper Opin Pharmacother 2008;9:363‐76.
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Genetic Testing Recommendations
• Genetic testing might be considered to identify
whether a patient at high risk for poor clinical
outcomes is predisposed to inadequate platelet
inhibition with clopidogrel (Class IIb, LOC: C)
– When a patient predisposed to inadequate platelet
inhibition with clopidogrel is identified by genetic
testing, treatment with an alternative P2Y12 inhibitor
might be considered (Class IIb, LOC: C)
• Routine use of genetic testing to screen patient
with clopidogrel who are undergoing PCI is not
recommended (Class III, LOC: C)
Levine GN et al. Circulation 2011; 124:2574‐2609.
O’Gara PT et al. Circulation 2013;127:529‐55.
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Post‐Intervention Complications
• Bleeding (depending on site accessed)
• Dissection/ rupture of free wall, coronary artery
or aorta
• Stent thrombosis
• Papillary muscle rupture and mitral regurgitation
• Arrhythmias (particularly after
reperfusion/revascularization)
• Contrast‐induced nephropathy
JAMA 2013;310:189‐98.
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Case Continues
• AF is found to have 100% occlusion to mid‐
LAD and to the distal RCA
– Drug eluting stent placed x 2
• EF 25% post‐intervention, SBP dropped to 80’s
– Intra‐aortic balloon pump (IABP) placed for
hemodynamic support
• He remains unresponsive and the team comes
to you to ask about initiation of targeted
temperature management (TTM)
_____________________________________________________________________________________________________
Question 3: Which best describes TTM initiation
for AF?
A. AF should not be considered for TTM because he experienced
a ventricular fibrillatory (VF) arrest and most data shows
benefit in pulseless electrical activity (PEA).
B. AF should not be considered for TTM because of the total
resuscitation time.
C. AF should be considered a candidate for TTM; however he has
a mild transaminitis which is a contraindication to initiation of
TTM.
D. AF should be considered for TTM; however, his renal function
should be closely monitored because of his SCr and TTM
having the potential to worsen glomerular filtration.
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TTM following Cardiac Arrest
• Comatose adult patients (lack of meaningful response to verbal
commands) with ROSC after cardiac arrest should have TTM
– Class I, LOE B‐R for VF/pVT out‐of‐hospital cardiac arrest
– Class I, LOE C‐EO for non‐VF/pVT (i.e., non‐shockable) and in‐hospital
cardiac arrest
• Select and maintain a constant temperature between 32 ‐ 36°C
during TTM (Class I, LOE B‐R)
– Maintain TTM for at least 24 hours after achieving target temperature
(Class IIa, LOE C‐EO)
• Patients should not undergo prehospital cooling after ROSC
with a rapid infusion of cold IV fluids (Class III: No benefit, LOE
A)
• May be reasonable to actively prevent fever in comatose
patients after TTM (Class IIb, LOE C‐LD)
VF= ventricular fibrillation
pVT= pulseless ventricular tachycardia
Callaway CW et al. Circulation. 2015; 132(suppl 1):s465‐482.
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Hypothermia After Cardiac Arrest
60
Study Group Primary Endpoint
p=0.009 p=0.02
50
Percentage of patients (%)
40
30 Normothermia
Hypothermia
20
10
0
Favorable Neurologic Recovery Death
Hypothermia After Cardiac Arrest Study Group. N Engl J Med. 2002; 346:549‐56.
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Bernard et al. Primary Endpoint
25
Percentage of Patients (%)
20
15
10
Normothermia
5
Hypothermia
0
Bernard SA et al. NEJM. 2002; 346:557‐63.
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Targeted Temperature Management
(TTM) Trial
950 unconscious adults after out‐of‐hospital cardiac arrest w/ presumed cardiac cause
with sustained ROSC
Randomized, international trial involving 36 ICUs in Europe and Australia
R
1:1
476 subjects assigned to 474 subjects assigned to
TTM 33⁰C TTM 36⁰C
472 subjects included per 464 subjects included per

protocol analysis protocol analysis
Gradual rewarming after 28 hr to 37⁰C in 0.5 ⁰C increments
Body temperature maintained at 37.5⁰C for 72 hrs post arrest
Primary Outcome: All‐cause mortality
Secondary Outcomes: Composite of poor neurologic function or death at 180 days
Nielsen N et al. NEJM. 2013; 369:2197‐206.
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TTM Outcomes
100
90
80
70
p=0.51 p=0.78 p=0.87 p=0.92
Outcome (%)
60
50
33⁰C Group
40
36⁰C Group
30
20
10
0
Death* CPC of 3‐5 Modified Rankin Death at 180
4‐6 days
*Primary endpoint
CPC= Cerebral performance category
(scale of 1‐5, 1= good cerebral performance, 5= severe disability) Nielsen N et al. NEJM. 2013; 369:2197‐206.
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TTM Conclusions
• No significant differences in overall mortality or in
the composite neurologic outcome or death at
180 days
– One or more serious ADE occurred in the 33⁰C group
(93%) compared with the 36⁰C group (90%), p=0.09
with hypokalemia being more frequent (p=0.02)
• Limitations: not fully blinded, consent not
obtained, and limited data regarding dose/type of
sedation and NMBA used
Nielsen N et al. NEJM. 2013; 369:2197‐206.
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TTM Patient Selection
• Comatose state with lack of meaningful response to
verbal commands
• Variability in the following:
– Initial rhythm
– Witnessed or unwitnessed arrest
– In‐hospital vs out‐of‐hospital
– Time to basic life support (BLS)
– Total ischemic time
– Time since ROSC
– Baseline body temperature
– Etiology of arrest
– Hemodynamic parameters
– Exclusion Criteria
McNicol DR et al. Circulation. 2012; 126:A56.
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Effects of Targeted Temperature
Management (TTM)
• Protective
– Reduce cerebral metabolism, cerebral blood flow,
ion pump dysfunction and neuroexcitation,
mitochondrial injury
– Decrease intracellular acidosis, intracranial
hypertension, free radical production and
apoptosis
Polderman K. Crit Care Med. 2009; 37[suppl]:s186‐s202.
_____________________________________________________________________________________________________
Time Course of TTM
Induction Maintenance Rewarming
Phase Phase Phase
Goal: To reduce the patient’s Goal: To tightly control the Goal: To rewarm the patient

body temperature to goal as patient’s core body temperature in a slow and controlled
fashion at 0.2 to 0.5 ºC per hour
quickly as possible with a maximum fluctuation of
0.2‐0.5ºC  Risks associated with rapid
 Cold IV fluids, ice packs, rewarming
internal and external cooling  Continue deep sedation until
devices at target temperature
 Ensure adequate sedation
 Complications: shivering and
seizures
Polderman KH et al. Critical Care Med. 2009; 37:1101‐20.
_____________________________________________________________________________________________________
Cooling Methods
• Cold normal saline (4⁰C)/ intravenous or gastric lavage
– 30‐40 mL/kg
– Limitations: lack of control, risk of overcooling, volume
• Ice packs and cooling blankets
– Advantages: low cost
– Limitations: low cooling rate, skin damage, difficulty with temperature
maintenance, nursing care
• Hydrogel‐coated cooling pads
– Advantages: temperature maintenance, use with routine care
– Limitations: high cost, skin complications (rare)
Seder DB, et al. Crit Care Med. 2009; 37(7 Suppl):S211‐22.
Hegazy AF, et al. BMC Anesthesiology 2015;15:152‐7.
_____________________________________________________________________________________________________
Cooling Methods (Cont’d)
• Intravascular cooling
– Advantages: temperature control, ?decreased shivering
– Limitations: complications (vascular injury, infection, thrombosis),
expensive
• Esophageal cooling
– Advantages: ease of placement, precise temperature control, does not
interfere with interventions
– Limitations: administration of oral medications, tube to intermittent
suction, cannot use history of esophageal varices or malformation
Seder DB, et al. Crit Care Med. 2009; 37(7 Suppl):S211‐22.
Hegazy AF, et al. BMC Anesthesiology 2015;15:152‐7.
_____________________________________________________________________________________________________
Question 4: Which of the following
pharmacokinetic / pharmacodynamic
alterations occurs with TTM?
A. Increased renal perfusion
B. Increased gastric motility
C. Decreased bleeding times
D. Decreased hepatic clearance
_____________________________________________________________________________________________________
TTM Pharmacokinetic Alterations*
• Absorption
– Slow rate of availability
– Delayed onset– prolongation of time to Cmax
– Reduction in gastric motility= variability with oral dosage forms
• Distribution
– Vd dependent upon blood flow redistribution and blood pH
(increased and pCO2 decreased)
– Alterations in protein binding
– Lipid solubility
– Tissue binding capacity
Alterations in Pharmacokinetics and Pharmacokinetics in Critical Care
Van den Broek M et al. Clin Pharmacokinet. 2010; 49:277‐94.
_____________________________________________________________________________________________________
TTM Pharmacokinetic Alterations
• Metabolism
– Altered temperature = altered enzymatic function
– Less activation or inactivation of drug and metabolites
— Prolonged conversion of prodrug to active drug
— Higher serum concentrations of active compounds= toxicity
— Accumulation of active metabolites
• Elimination
– Impaired hepatic blood flow and decreased biliary clearance
– Renal perfusion decreased
– Impaired CrCl during maintenance phase and reversed upon
rewarming
– Increased urine output thought to be due to a cold diuresis
Van den Broek M et al. Clin Pharmacokinet. 2010; 49:277‐94.
_____________________________________________________________________________________________________
Drugs and Altered PK/PD in TTM
Drug Therapeutic Effect
Fentanyl ↓CL, ↑ Plasma concentra ons
Morphine ↓ receptor aﬃnity
Midazolam ↓CL, ↑Css and Vd
Propofol ↓CL, ↑ Plasma concentra ons
Rocuronium ↓ CL, ↑dura on of ac on
Vecuronium ↓CL,↑ Dura on of ac on
Cisatracurium ↑ Dura on of ac on
Phenytoin ↑AUC, ↓CL and ke
Tortorici MA et al. Crit Care Med. 2007; 35:2196‐204.
_____________________________________________________________________________________________________
Case Continues
• The patient is 4 hours into the maintenance
phase of TTM
• Current IV infusions include:
– Norepinephrine 10 mcg/min
– Phenylephrine 125 mcg/min
– Fentanyl 200 mcg/hr
– Midazolam 4 mg/hr
_____________________________________________________________________________________________________
Question 5: The patient shows no signs of
shivering although the cooling machine water
temperature continues to decrease. Which of
the following would be the best option to
manage shivering if it occurs in this patient?
A. Increase fentanyl infusion rate to 250 mcg/hr
B. Increase midazolam infusion rate to 5 mg/hr
C. Add vecuronium IV pushes 0.1 mg/kg every 4 hr PRN
shivering
D. Add cisatracurium 0.1 mcg/kg/min by continuous IV infusion
_____________________________________________________________________________________________________
Complications of TTM
• Acid/ base derangements
• Bleeding/platelet dysfunction
• Cardiovascular
– Risk of ventricular tachycardia/fibrillation, decreased cardiac output
and decreased heart rate
• Electrolyte abnormalities
• Hemodynamic (ECG, BP, HR) changes
• Hyperglycemia
• Infection
• Platelet dysfunction
• Shivering
• Seizures and myoclonus
• Urine output increased and decreased CrCL
Empey PE, et al. Crit Care Med. 2013; 41:2379‐87.
Perbert S, et al. Am J Respir Crit Care Med. 2011; 184:1048‐54.
Geurts M, et al. Crit Care Med. 2014; 42:231‐42.
_____________________________________________________________________________________________________
Management of Shivering
• Pharmacologic treatment
– Acetaminophen
– Neuromuscular blocking agents
– Opiates and sedatives
– Magnesium
– Clonidine
– Buspirone
• Nonpharmacologic treatment
– Head and hand warming
– Warming blankets
Bjelland T, et al. Intensive Care Med. 2012; 38:959‐67.
_____________________________________________________________________________________________________
Shivering Controversies
• Shivering assessment
– Shivering is not always visible to “score”
– Monitoring water temperature of cooling device
• Lack of reliability with train of four monitoring
– Risk of excessive paralysis
– Use clinical monitoring or continuous
electroencephalography (EEG)
• Consideration of bolus dosing vs. continuous infusion
for opiates, benzodiazepines and paralytics
• Outcome data with drug selection?
May TL et al. Neurocrit Care. 2014 June 25 [Epub ahead of print].
Burjek NE et al. Crit Care Med. 2014; 1204‐12.
Salciccioli JD et al. Resuscitation. 2013; 84:1728‐33.
_____________________________________________________________________________________________________
Neurologic Complications
• Sedation and Analgesia Strategies
– Adequate pain control and sedation must be
employed
– Target Richmond Agitation and Sedation Scale (RASS)
score of ‐3 to ‐5 with evidence of shivering
– Risk of accumulation of parent and active metabolites
• Seizures
– Benzodiazepines should be used first line
– Phenytoin, barbiturates, valproic acid, and propofol
can be used cautiously with monitoring
Polderman KH et al. Crit Care Med. 2009; 37(3):1101‐20.
_____________________________________________________________________________________________________
Cardiovascular Complications
• Arrhythmias
– Ventricular tachycardia (VT), VF, and atrial fibrillation
– Sinus bradycardia should not be treated unless it leads to
hemodynamic instability
— If life threatening consider discontinuation of therapeutic
hypothermia and active rewarming
• ECG abnormalities
– Prolonged PR, QRS, and QT intervals
— Medications that prolong the QT interval should be used
cautiously
• Hemodynamic abnormalities
– Decreased cardiac output
Polderman KH, et al. Crit Care Med. 2009; 37(3):1101‐20.
Tiainen M, et al. Crit Care Med. 2009; 37:403‐9.
_____________________________________________________________________________________________________
Hematologic Complications with TTM
• Coagulopathy caused by:
– Impaired activation and activity of clotting factors
– Thrombocytopenia
– Impaired platelet dysfunction
• Patients with active bleeding should not
undergo initiation of TTM
Polderman KH, et al. Crit Care Med. 2009; 37(3):1101‐20.
_____________________________________________________________________________________________________
Case Continues
• AF has reached target temperature of 33 Celsius
and the team asks you your recommendation to
initiate heparin infusion for the risk of thrombosis
from the intra‐aortic balloon pump. The baseline
PTT is 33 sec (range 25‐35 sec).
• A cardiac/moderate intensity heparin protocol is
selected with a recommended initial bolus of 60
units/kg and infusion to start at 12 units/kg/hr
_____________________________________________________________________________________________________
Question 6: Which of the following best describes
your recommendation?
A. Administer 60 unit/kg intermittent bolus doses of UFH and
repeat PTTs every 6 hours
B. Administer an initial 60 unit/kg bolus dose of UFH followed by
a 12 unit/kg/hr continuous infusion with no reduction
C. Administer a 12 unit/kg/hr continuous infusion at a reduced
rate only without an initial bolus
D. Administer an initial but reduced 30 unit/kg bolus dose of UFH
followed by a continuous infusion at a reduced initial rate of 6
units/kg/hr
_____________________________________________________________________________________________________
Anticoagulation with TTM
• Coagulation cascade is dependent on enzymatic reactions
resulting in a prolonged PTT
– UFH
— PTT prolongation from 36±0.7 seconds at 37⁰C to 46.1±1.1 seconds at
31⁰C in 10 volunteers
— Retrospective review demonstrated an increase in PTT 2.5x ULN in
patients undergoing TTM at a temperature <35.5 ⁰ C
— Average UFH starting rate 13 ± 4 units/kg/hr. PTT above target in 89%
of patients with avg baseline, TTM and post TTM PTT 34±12, 142±48,
56±17 seconds, respectively.
– Management
— Bedside activated clotting time (ACT) or PTT with cooled blood
— Reduction of bolus dose and maintenance infusion rate of UFH
Rohrer MJ et al. Crit Care Med. 1992; 33:671.
Dalal BD et al. Chest. 2009; 136:41S.
Wahby KA et al. Resuscitation. 2014; 85:533‐7.
_____________________________________________________________________________________________________
Antiplatelet Management with TTM
• Platelet dysfunction as a result from hypothermia shown in vitro
– Concerns for stent thrombosis with variable platelet inhibition
• Aspirin
– Thromboxane A2 and thrombin‐induced platelet aggregation inhibited
— Effect shown to be reversed upon rewarming
• P2Y12 Inhibitors
– Hypercoagulability induced ADP‐platelet aggregation
– Decreased enzymatic conversion from prodrug
– Alterations in oral absorption
• Ticagrelor has demonstrated more rapid and sustained activity compared with
clopidogrel
– Other studies have shown no difference
Bjelland TW et al. Resuscitation. 2010; 81:1627‐31.
Frelinger AL et al. Am J Cardiol. 2003; 92:1099‐1101.
Moudgil R et al. Can J Cardiol. 2014; 30:1396‐9.
_____________________________________________________________________________________________________
Antiplatelet Management with TTM
• GPI Use
– TTM augments platelet dysfunction with use of
eptifibatide and tirofiban
– No change seen with abciximab use
—Concern for duration of platelet inhibition and bleeding
Frelinger AL, et al. Am J Cardiol. 2003; 92:1099‐1101.
_____________________________________________________________________________________________________
Case Continues
• AF continues TTM in the maintenance phase
and remains in sinus rhythm with continued
vasopressor support
– Urine output continues to decrease to <10 mL/hr
– The following labs results are obtained and you
are asked about electrolyte replacement:
140 102 32
191 Magnesium: 1.4 mg/dL
3.1 22 2.47 Phosphorous: 1.4 mg/dL
_____________________________________________________________________________________________________
Question 7: Which of the following is the best
answer to initially replace electrolytes?
A. Administer magnesium sulfate IVPB 4 g x 1, KCl IVPB 40 mEq x 2,
followed by potassium phosphate IVPB 20 mmol x 1
B. Administer magnesium sulfate 4 g IVPB x 1 followed by KCl IVPB
40 mEq x 2 and then potassium phosphate IVPB 20 mmol x 1
C. Administer magnesium sulfate IVPB 2 g x 1, followed by
potassium phosphate IVPB 30 mmol x 1
D. Administer magnesium sulfate IVPB 4 g x 1, followed by
potassium phosphate 40 mmol x 1
_____________________________________________________________________________________________________
Electrolyte Disorders in the ICU
• Hypokalemia (<3.5 mEq/L)
– Results from intracellular shifts, increase loss,
decreased ingestion and drug administration
—Increased wasting of potassium due to increased urine
output and intracellular shift during TTM
– Serum potassium levels may not correlate with total
body potassium
—Metabolic alkalosis can cause an intracellular shift but the
total body potassium does not change
• For every 0.3 mEq/L decrease in serum potassium
concentration, the total body deficit is 100 mEq/L
Kraft MD et al. Am J Heath Syst Pharm. 2005; 62:82.
_____________________________________________________________________________________________________
Hypokalemia Management in the ICU
• Goal: Maintain serum potassium 3.5‐5 mEq/L
– Renal impairment: replace no more than 50% of
the recommended initial dose
• Monitoring: recheck level every 1‐6 hours in
symptomatic patients with severe hypokalemia
Severity Serum Potassium IV Potassium Replacement
Concentration (mEq/L) Dose (mEq)
Mild to Moderate 2.5‐3.4 20‐40
Severe <2.5 40‐80
Kraft MD, et al. Am J Heath Syst Pharm. 2005; 62:82.
_____________________________________________________________________________________________________
• Hypomagnesemia (<1.5 mg/dL)
– Results from excessive GI and renal losses,
surgery, trauma, infection, sepsis, burns,
alcoholism, starvation, malnutrition, drug
administration
– Associated with an increased mortality in the
critically ill
– Extracellular magnesium stores do not correlate
with intracellular stores
_____________________________________________________________________________________________________
Hypomagnesemia
• Goal: Avoid or resolve symptoms and maintain serum
magnesium concentrations of 1.5‐2.4 mg/dL
– Renal impairment: replace no more than 50% of the
recommended initial dose
– Patients with ACS should have concentrations greater than 1.7
mg/dL to prevent cardiac arrhythmia
– Replacement is empirical
• Monitoring: At least daily during repletion
Severity Serum Magnesium IV Magnesium Replacement
Concentration (mg/dL) Dose (g)
Mild to Moderate 1‐1.5 1‐4 g (up to 1 mEq/kg)
Severe <1.0 4‐8 g (1.5 mEq/kg)
Kraft MD et al. Am J Heath Syst Pharm. 2005; 62:82.
_____________________________________________________________________________________________________
• Hypophosphatemia (<2.7 mg/dL)
– Results from malnutrition, inadequate body stores
or administration, metabolic and respiratory
alkalosis, diabetic ketoacidosis, alcoholism,
vomiting or gastric losses, and drug administration
– Severe depletion can cause respiratory failure,
weakness, paralysis, neurologic dysfunction and
death
_____________________________________________________________________________________________________
Hypophosphatemia
• Goal: Maintain serum phosphorous of 2.7‐4.5 mg/dL
– Replacement dependent upon if the patient is symptomatic
– Patients with renal impairment not being treated with CRRT
administer <50% of the initial dose
• Monitoring: Check levels 2‐4 hr after administration and
treat until the patient is asymptomatic
Serum Phosphorous Concentration (mg/dL) IV Phosphorous Replacement Dose
(mmol/kg)
2.3‐2.7 0.08‐0.16
1.5‐2.2 0.16‐0.32
<1.5 0.32‐0.64
_____________________________________________________________________________________________________
Electrolyte Imbalances in TTM
• Conservative replacement of potassium,
magnesium and phosphorous during
maintenance phase
– Frequent monitoring recommended
—Potassium >3.5 mEq/L
—Magnesium >2 mg/dL
—Phosphorus as needed
– Discontinue supplementation when rewarming
—Avoid potassium repletion 4 hr prior to rewarming
unless <3.5 mEq/L
Noyes AM, et al. J Intensive Care Med. 2013; 1‐11.
_____________________________________________________________________________________________________
Glucose Management with TTM
• What we know
– Insulin requirements increase during maintenance
phase of TTM
– Insulin requirements decrease during the rewarming
phase
—Need for more frequent blood glucose monitoring
– Goal should be <180 mg/dL without causing
hypoglycemia
• What we don’t know
– No consensus on management
– Blood glucose target
Polderman KH et al. Crit Care Med. 2009; 37(3):1101‐20.
_____________________________________________________________________________________________________
Summary of TTM
• Maintenance Phase
– Goal temperature selection
– Is the effect due to TTM or the medication?
– Careful monitoring of HR, BP, RR, SVO2, ECG
– Consideration for obtaining drug levels
– Reduction of loading doses
– Consider bolus dosing over continuous infusions
• Rewarming Phase
– Consider dose adjustments and more frequent serum drug
monitoring upon rewarming
• Life‐threatening arrhythmias or coagulopathy resulting in
bleeding suggest need to discontinue TTM
Noyes AM, et al. J Intensive Care Med. 2013; 1‐11.
_____________________________________________________________________________________________________
Case Continues
• AF’s IABP continues at 1:1 and SBP drops into the 70’s*
– Continued vasopressor support
— Norepinephrine 20 mcg/min
— Epinephrine 10 mcg/min
— Vasopressin 0.04 units/min
— Dobutamine 5 mcg/kg/min
– Progressive respiratory failure despite optimal ventilatory
support
— Oxygen saturation in the low 80’s
– Decreased UOP < 10ml/hr and SCr continues to increase
– Worsening metabolic acidosis, pH 7.1, lactate 3.1 mmol/L
Pharmacotherapy Considerations in Management of Shock
_____________________________________________________________________________________________________
Question 8: Which of the following would be the
next step in providing hemodynamic support for
this patient?
A. Veno‐arterial (VA) ECMO
B. Veno‐venous (VV) ECMO
C. Percutaneous left ventricular assist device
D. Continue current management with IABP
_____________________________________________________________________________________________________
Mechanical Circulatory Support
• Intra‐aortic balloon pump
– Temporary device that assists with improving cardiac output during deflation
and improving vital organ and coronary perfusion during inflation
— 1:1 = one inflation/deflation per heart beat (maximal support)
— 1:4= one inflation/deflation per heartbeat (less support)
– As duration of deflated time increases the thrombosis risk increases, thus
anticoagulation is required
• Percutaneous ventricular assist device
– Temporary device considered in cardiogenic shock or as temporary support during a
high‐risk cardiac intervention
– Requires anticoagulation due to risk of thrombosis
• Extracorporeal membrane oxygenation (ECMO)
– Similar to coronary artery bypass where blood passes through an oxygenator and is
cleared of carbon dioxide and then actively pumped back into the body
— Venoarterial (VA)
— Venovenous (VV)
• Implantable ventricular assist devices
_____________________________________________________________________________________________________
Indications and Goals for ECMO
• Cardiac failure
• Respiratory failure
• Cardiac and respiratory failure
• High‐risk cardiac catheterization procedures
• Goal: support of cardiac and pulmonary
systems allowing time for treatment and
recovery from the underlying problem
Brodie D, et al. N Engl J Med 2011; 365:1905‐14.
_____________________________________________________________________________________________________
Indications by Modality
• Respiratory Support • Hypoxic Respiratory Failure
• Hypercapnic Respiratory Failure
– VV ECMO
• Bridge to Transplant
– VA ECMO
• Hemodynamic Support • Cardiac Arrest
• Cardiogenic Shock
– VA ECMO • Acute RV Failure
• Failure to wean cardiopulmonary
bypass after surgery
• Bridge to transplant
_____________________________________________________________________________________________________
Contraindications to ECMO
• Cannot be anticoagulated
• Metastatic malignancy
• Non‐curable chronic extrapulmonary infection
• Hepatitis B, Hepatitis C, HIV
• Untreatable advanced dysfunction of another
organ
• Poor nutritional status/rehabilitation potential
• Significant psychosocial problems
Makdisi G, Wang I. J Thorac Dis 2015; 7(7):E166‐176.
_____________________________________________________________________________________________________
Patient Management on VV‐ ECMO
• Lung protective strategy
– Low FiO2
– Low airway pressures
• Use ECMO to control pO2 and pCO2
• Speed– adjusts flow
– Veno‐venous is not a ‘pump’
– Maintain enough flow to oxygenate blood and keep
blood through circuit
• Weaning– may wean ventilator or ECMO first,
dependent on patient status
_____________________________________________________________________________________________________
Patient Management on VA‐ECMO
• Hemodynamics
– Mean arterial pressure (MAP) goal 70‐90 mm Hg
— Maintain low flow
– Pulsatility with inotropes and vasopressors
– Central venous pressure (CVP)
— Fluids or diuretics to goal weight
– Oxygen saturation
– Goal flow with ejection (cardiac output)
• Ventilator
– Oxygenation
– Minimize FiO2 and titrate sweep for pCO2 35‐45 mm Hg
– Lung protective strategy
— Minimal tidal volume
_____________________________________________________________________________________________________
PK/PD Changes with ECMO
• Most data are limited to neonatal population
• Potential for PK of all drugs to be altered
– Sedatives, analgesics and antimicrobial agents
• Critically ill patients PK/PD already altered
• ECMO can:
– Sequester drugs in ECMO circuit
– Increase Vd
– Decrease drug elimination
Ha M, Sieg A. Pharmacotherapy 2017; 37(2):221‐235.
Buck ML, et al. Clin Pharmacokinet 2003; 42:403‐17.
_____________________________________________________________________________________________________
Pharmacokinetic Changes
ECMO
SIRS*, ↑CO Hemodilution Fluid Drug Sequestration Organ Dysfunction

Shifts
↑CL ↑Vd ↓CL
Low Plasma High Plasma
Concentrations Concentrations
Therapeutic Failure Toxicity
*SIRS‐ Systemic Inflammatory Response Syndrome
Shekar K, et al. J Crit Care 2012; 27:741.e9‐18.
_____________________________________________________________________________________________________
Drug PK in ECMO
• Circuit Factors/ Drug Factors • Patient Factors/ Critical illness
– Drug sequestration: circuit – Serum protein
— Circuit tubing — Drug binding
— Membrane oxygenator
— Tissue uptake
– Drug sequestration: drug
— Lipophilicity – Acid‐base disorders
— Protein binding — Ionization
— Molecular size — Protein binding
— Ionization – Volume status
– Circuit priming — Total body water
— Fluid type
— Fluid pH — Adipose tissue
— Electrolytes – Organ dysfunction
— Temperature — Renal injury
– Circuit Age — Renal replacement therapy
— Prior drug exposure — Hepatic injury
— Saturation
Shekar K, et al. J Crit Care. 2012; 27:741.e9‐18.
_____________________________________________________________________________________________________
Volume of Distribution
• Altered/increased Vd by several mechanisms
– SIRS, ↑CO, hemodilution/fluid shifts, drug
sequestration, organ dysfunction
• Higher proportion of total body water
– Higher Vd for hydrophilic drugs (β‐lactams and
aminoglycosides)
• Decreased plasma protein binding, increases
unbound drug concentrations increases Vd
• Up‐regulation of renin‐angiotensin‐aldosterone
system leading to increased circulating blood volume
and Vd
_____________________________________________________________________________________________________
Drug Clearance
• Decreased elimination can lead to elevated plasma
concentrations
• Reduced drug elimination by
– Renal dysfunction
– Liver dysfunction
• Decreased pulmonary blood flow (VA‐ECMO)
– Affects sequestration and metabolism by the lungs
_____________________________________________________________________________________________________
Case Continues
• It has been 24 hours since VA‐ECMO started and AF is
breathing over the ventilator.
• Current infusions include:
– Fentanyl 200 mcg/hour
– Midazolam 8 mg/hour
– Cisatracurium 3 mcg/kg/min
– Norepinephrine 20 mcg/min
– Epinephrine 4 mcg/min
– Phenylephrine 50 mcg/min
– Dobutamine 2.5 mcg/kg/min
– UFH 7 units/kg/hour
– Insulin infusion per protocol
_____________________________________________________________________________________________________
Question 9: Which of the following is the best
sedation management strategy for this patient?
A. Administer a fentanyl bolus and increase the infusion rate
B. Administer a midazolam bolus and increase the infusion rate
C. Discontinue midazolam infusion and initiate a propofol infusion
at 40 mcg/kg/min
D. Discontinue midazolam infusion and initiate a
dexmedetomidine infusion at 0.4 mcg/kg/hr
_____________________________________________________________________________________________________
Sedation/Analgesia Management
• Goals: Provide light sedation w/ daily interruption
and minimize use of neuromuscular blocking
agents (NMBA)
• ECMO Considerations
– Minimize risk of catheter malposition or accidental
dislodgement and coughing
– Deep sedation +/‐ paralysis may be warranted to
optimize circuit flows and ventilation to minimize
oxygen consumption
• ECMO PK/PD = substantially higher
sedative/analgesic doses to obtain desired effect
_____________________________________________________________________________________________________
Sedation and Analgesia PK
Protein
Medication Vd Effect Dose Adjustment
Binding
Midazolam 97% 70‐217 L Significant amount of Increased dose required
drug sequestered (97%
at 24 hr)
Dexmedetomidine 94% 118 L ~40% loss in circuit at Increased starting dose
60 min may be required
Propofol 95‐99% 4200 L 70% loss in circuit at 45 Increased dose may be
min required
Fentanyl 79‐87% 280‐420 L Significant drug loss at Escalating dose required
24 hr
Morphine 20‐35% 70‐350 L Minimal to moderate May be required
amount of drug
sequestered
_____________________________________________________________________________________________________
ECMO‐Associated Coagulopathy
• Increased risk of thrombotic complications
– Alterations in coagulation cascade due to oxygenator,
circuit and turbulence through ECMO pump
• High risk of bleeding due to anticoagulant use,
fibrinolytic state and large‐bore cannula
• Need for anticoagulation, frequent monitoring
and replacement of clotting factors
– UFH, argatroban or bivalirudin use (patients with
heparin‐induced thrombocytopenia)
Bartlett et al. Miverva Anes 2010; 76:534‐40.
Pieri M, et al. J Cardiothorac Vasc Anesth 2013;27:30‐4.
Young G, et al. Perfusion 2004;19:283‐8.
_____________________________________________________________________________________________________
ECMO Anticoagulation
• PK/PD Considerations:
– >50% of administered heparin is eliminated by the
extracorporeal circuit itself or by blood components in the
circuit
• Need for close monitoring and replacement of
specific factors if needed
– Consideration of antithrombin III administration in
those with heparin “resistance”
• Monitoring – multiple can be considered
– ACT, aPTT are most commonly used
— Anti‐xa or thromboelastography (TEG)
Byrnes JW, et al. ASAIO J 2014;60:57‐62.
Marasco S, et al. Heart, Lung and Circulation 2008; 17S:S41‐47.
Shekar K, et al. J Crit Care 2012; 741(27):e9‐18.
_____________________________________________________________________________________________________
ECMO Bleeding Complications
• Occurs in 30‐50% of patients and is due to
continuous anticoagulation and platelet dysfunction
• Management:
– Avoid or minimize all non‐urgent invasive procedure
– Adjust anticoagulation infusion/ monitoring goals
– Transfuse platelets
– Antifibrinolytics, FFP, or specific clotting factors may be
indicated
Marasco S, et al. Heart, Lung and Circulation 2008; 17S:S41‐47.
_____________________________________________________________________________________________________
ECMO Conclusions
• ECMO is a temporary mechanical circulatory
support in those with severe cardiac and/or
pulmonary dysfunction
• Careful monitoring of the circuit is needed to
prevent coagulopathies and bleeding
• Optimal drug dosing remains largely unknown for
a variety of agents
– Monitor efficacy with drug levels where appropriate
– Consideration of organ function pre‐ and post‐ECMO
initiation
_____________________________________________________________________________________________________
Complex Case:
Acute Coronary Syndrome
Jill H. Starykowicz, Pharm.D., BCCCP
Clinical Pharmacy Specialist, Cardiology/ Critical Care
Advocate Lutheran General Hospital
Park Ridge, Illinois
_____________________________________________________________________________________________________

CCRC AcuteCoron Slides T199174 Final-1up

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Complex Case:

Cardiac Enzymes Positive Cardiac Enzymes Positive Cardiac Enzymes Negative

Wallentin L et al. N Engl J Med. 2009; 361:1045-57.

BRAVE‐4 Two arms: Composite death, Trial stopped early Composite: bivalirudin

472 subjects included per 464 subjects included per

Goal: To reduce the patient’s Goal: To tightly control the Goal: To rewarm the patient

SIRS*, ↑CO Hemodilution Fluid Drug Sequestration Organ Dysfunction

↑CL ↑Vd ↓CL

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